Pj. Swart et al., The metabolic fate of the anti-HIV active drug carrier succinylated human serum albumin after intravenous administration in rats, J DRUG TAR, 9(2), 2001, pp. 95
The pharmacokinetics and metabolic fate of the intrinsically active (anti-H
IV) drug carrier succinylated human serum albumin (Suc-HSA) was studied in
rats. Suc-HSA was prepared by derivatizing HSA with 1,4-[C-14]-succinic anh
ydride, a modification by which all available epsilonNH2-groups in HSA were
converted into carboxylic groups.
After iv injections of 0.3, 1.0, 3.0 and 10.0 mg/kg in freely moving rats,
Suc-HSA showed a dose dependent elimination pattern, indicating a saturable
elimination pathway. The Michaelis-Menten parameters V-max and K-m were 98
.7 mug.min(-1).kg(-1) and 8.5 mug.ml(-1) respectively. The kinetics of Suc-
HSA was influenced by anaesthesia. In anaesthetised animals, V-max and K-m
were found to be 26.9 mug.min(-1).kg(-1) and 0.26 mug.ml(-1), respectively.
This implies an intrinsic clearance of 100 ml.min(-1).kg(-1), which is abo
ut 10-fold higher as compared to 12 ml.min(-1).kg(-1) in freely moving anim
als.
Intravenous administration of a sub-saturable dose of 3.0 mg.kg(-1)1,4-[C-1
4]-Suc-HSA to freely moving rats resulted in a biphasic elimination with an
initial t(1/2) of 20 min and a terminal t(1/2) of 40 hrs. Excretion of met
abolites in urine and faeces lasted for at least 48 hours. About 70% of the
radioactive dose was excreted in urine, whereas maximally 2% was detected
in faeces. Suc-HSA was degraded to its individual amino acids including suc
cinylated lysine (the only radioactive product formed). Succinylated lysine
was not further metabolised and mainly excreted via the urine. Immunohisto
chemical staining showed that even after 48 hrs Suc-HSA could be detected i
n livers. Together with the urinary excretion patterns, this points to a gr
adual degradation of Suc-HSA.